Transfusion is a life-saving therapy, given to a large number of patients for a wide variety of medical indications. In the United States of America alone, approximately 5 million patients (i.e. 1 out of every 70 Americans) are transfused with red blood cells (RBCs) each year. In addition to the well-known ABO and RhD blood group antigen systems, there are in excess of 300 known RBC antigens that vary from person to person. Thus, any non-autologous transfusion represents an exposure to a multiplicity of antigenic differences. The immune system of some transfusion recipients will react to the foreign alloantigens and generate alloantibodies. Once a patient has an antibody against an RBC alloantigen, then they are designated “incompatible” with donor RBCs that express that antigen.
Transfusion of incompatible blood is avoided, because the antibodies can destroy the transfused RBCs. The major problem is not just that destroying the RBCs obviates the potential therapeutic effect, but more importantly, the process of RBC destruction by recipient antibodies can be a profound toxic insult to the recipient, leading to myriad pathological outcomes, including: electrolyte disturbance, hemodynamic dysregulation and instability, kidney failure, coagulopathy, and death in extreme cases. In aggregate, these pathologies are referred to as a hemolytic transfusion reaction (HTR). Avoiding HTRs is the primary goal of blood banks around the world, and represents an entire field of immunohematology (e.g. characterizing patient alloantibodies as they evolve with each transfusion, and providing compatible RBCs not recognized by a patient's antibodies).
The majority of transfused patients are typically being treated for an injury or transient illness, from which they subsequently recover, and no longer require transfusion. In such patients, avoiding incompatible transfusion is an issue of blood bank logistics, and sufficient RBCs can be provided to such patients by monitoring the antibody response as it evolves and identifying/acquiring units of RBCs lacking the antigens to which the patients have alloantibodies. However, a subset of patients require chronic transfusion therapy, in some cases for the remainder of their lives. For example, genetic abnormalities in RBC production (mostly hemoglobinopatheis) lead to lifelong needs for RBC transfusion support (e.g. Sickle cell disease (SCD), alpha and beta thallesemia, Dianond Blackfan anemia, Faconi anemia, etc). As an example, patients with SCD often have weekly prophylactic transfusions, exposing them to a panoply of different antigens. Up to 50% of SCD patients become alloimmunized to at least one alloantigen, and once a patient becomes immunized to one alloantigen, they are more likely to become immunized to additional antigens. Rates of alloimmunization can be mitigated by prematching to select matched blood group antigens (e.g. Kell, Kidd, Duffy, and others), however such pre-matching is often not feasible and is very costly. In addition, the matching process can delay the delivery of blood, which may have significant negative consequences if the patient is being treated for a clinical crisis episode.
The more antigens against which a given patient becomes alloimmunized, the more difficult it becomes to find a sufficient number of compatible RBC transfusions to meet the patient's clinical needs. In some cases, compatible RBCs do not become available quickly enough to properly care for the patient, and in extreme cases, alloimmunized patients may die for wont of sufficient compatible RBCs.
A second disease that can result from patient alloimunization against RBC antigens is hemolytic disease of the fetus and newborn (HDFN). In this case, a pregnant mother has alloantibodies against an antigen expressed by a fetus she is carrying in her womb. The antibodies can cross the placenta, and destroy fetal RBCs, resulting in fetal anemia, maldevelopment, and in serve cases, death. In HDFN, the mother herself does not become anemic, as the alloantigen in question is not on her own RBCs, but only on those of the fetus. The frequency of HDFN has decreased with the use of anti-D Ig, however alloimmunization still occurs against RhD. Moreover, there is no prophylaxis currently available for antigens such as Kell, Kidd, Duffy etc. Once a woman is alloimmunized and pregnant with an antigen positive fetus, the primary treatment is intrauterine transfusions with RBC negative blood and symptomatic treatment.
The inability of current technologies to provide sufficient units of compatible RBCs for alloimmunized patients, resulting in morbidity and mortality due to lack of compatible blood, is a primary medical need addressed by the current disclosure. A secondary application of the present disclosure is for the treatment of pregnant women whose fetuses are suffering HDFN.